tbuckley/cabot-search huggingface dataset:
Targeting Replication Stress for Glioma Stem Cell Specific Cytotoxicity
Authors: Emily Clough, Karen Strathdee, Ross Carruthers
Journal: Neuro-Oncology (2022)

Abstract AIMS Glioma stem cells (GSC) show high levels of DNA replication stress and exhibit abnormal S phase in comparison to differentiated, non GSC tumour cells. We investigated the DNA replication phenotypes of GSC and mechanism of GSC specific cytotoxicity following DNA replication stress response inhibition with combined ATR/PARP inhibition (CAiPi). METHOD Paired GSC enriched (‘GSC’) and GSC deplete differentiated (‘bulk’) populations were cultured from resected GBM specimens and maintained in neurobasal media with growth factors or serum containing media respectively. Cell viability, neurosphere and clonogenic assays were used to assess cytotoxicity whilst DNA replication was interrogated utilising immunofluorescent repair foci, flow cytometry and DNA fibre assay. CAiPi consisted of VE821 (ATRi) with Olaparib (PARPi). RESULTS GSC show reduced DNA replication rates and alterations in cell cycle profile and demonstrate extreme sensitivity to CAiPi. CAiPi resulted in significantly elevated levels of 53BP1 nuclear bodies in GSC indicating genomic under- replication, however did not preferentially reduce fork speed compared to non-GSC. Analysis of replication fork structures revealed an increase in new origin firing in GSC dependent upon PARP trapping. GSC cytotoxicity was reduced by roscovitine induced inhibition of origin firing, suggesting an important role of dysregulated origin firing in CAiPi response. CAiPi is also potently radiosensitising by clonogenic assay. CONCLUSION Taken together these data suggest that GSC are vulnerable to dysregulation of origin firing which results in under-replication of their genome and reliance upon G1 cell cycle resolution of DNA damage. We propose that CAiPi is an attractive therapeutic strategy for translation to the clinic.
Awake Craniotomy Is Well-tolerated in the Elderly: Our Early Experience
Authors: Rosina Khan, Magnus Okoh, Ikenna Ogbu, Huan Chan, Erminia Albanese
Journal: Neuro-Oncology (2022)

Abstract AIMS Awake craniotomy for brain tumour resection aims to increase the extent of resection while minimising neurological deficit. The major concerns for patients during awake craniotomies include peri-operative discomfort/pain and anxiety for some patients. Older patients are generally not offered aggressive operative options due to longer lengths of hospital stay (LOS), expected higher rates of peri-operative morbidity/mortality, and poorer survival. However, increased extent of glioma resection is associated with greater overall and progression-free survival. Furthermore, previous studies have shown that awake craniotomies are well tolerated in elderly patients. This study aims to evaluate our experience in awake craniotomies for glioma resection in patients over 65 years old. METHOD Seventeen elderly patients who had undergone awake craniotomies at University Hospitals of North Midlands between 2015 and 2021 were included. Outcome measures included LOS, post-operative morbidity/mortality, and the difference between pre- and post-operative Hospital Anxiety and Depression scores (HADS). RESULTS There was an 11% operative mortality rate in our cohort. The average LOS was 5.7 days. The median pre- and post-operative score at 6 months was 1 indicating that there is no difference post-operatively. There was a positive net difference between pre- and post-operative anxiety/depression scores in our cohort. CONCLUSION Awake craniotomies are generally well tolerated among the elderly patients with unchanged post-operative performance status and improved HADS scores. These findings suggest that awake craniotomies should be offered to elderly patients if deemed appropriate.
Early Post-treatment Pseudo-continuous Arterial Spin Labelling Stratifies 12 Month Survival in Gliomas
Authors: Alice Maguire, Emeka Obasi, Julia Markus, Meetakshi Gupta, Michael Kosmin, Magdalena Sokolska, Harpreet Hyare
Journal: Neuro-Oncology (2022)

Abstract AIMS Arterial spin labelling (ASL) is a non-invasive perfusion technique that uses endogenous contrast and is proving to be of value in paediatric neuro-oncology. ASL derived rCBV has been shown to correlate with Dynamic Susceptibility Contrast (DSC) -derived CBV and could be an alternative perfusion technique when DSC is not possible. The aim of the study was to investigate whether early post-treatment tumour ASL can stratify patient survival at 12 months. METHOD 180 consecutive patients diagnosed with glioblastoma and undergoing treatment between 2017-2021 were imaged with an extended MRI protocol that included pseudo-continuous ASL (pCASL). Patients that were imaged with pCASL within 1-3 months of completing radiotherapy were identified retrospectively. Scanner generated Perfusion weighted images were inspected and regions of interest encompassing the tumour were generated and compared with a control region in the contra-lateral grey matter. Overall survival data was collated and a comparison of tumour ASL was assessed with t-test statistics between patients surviving &amp;lt; and &amp;gt;12 months. RESULTS 43 patients were identified (23 male, median age 58 years, diagnoses: IDHwt-GBM 17, IDHmut-Astrocytoma 13, IDHmut 1p19q co-deleted Oligodendroglioma 13). Tumour ASL was 3.22 (± 2.1) in patients that survived less than 12 months compared to 1.64 (± 1.9) in patients that survived greater than 12 months, p=0.02). CONCLUSION Early post-treatment ASL can stratify patient survival at 12 months and show promise as an alternative to DSC perfusion in the prognostication of patients being treated for glioma.
Patient and Service User Representation in Language Assessments on an Awake Craniotomy Pathway
Authors: Georgette Smith, Ismail Ughratdar, Victoria Wykes, Camilla Dawson
Journal: Neuro-Oncology (2022)

Abstract AIMS Awake craniotomy (AC) with language mapping facilitates maximal safe intracranial tumour resection whilst preserving neurological function [1], and is associated with increased postoperative patient satisfaction and quality of life [2, 3]. We examine patients’ preoperative language assessment scores, alongside cultural and sociodemographic information to consider the impact on surgical planning and patient outcomes. METHOD A service evaluation of assessment tools was undertaken using clinical note audit and clinician reflections. Retrospective data collection from 48 patients assessed for AC with language mapping included language assessment scores, cultural and sociodemographic data, and surgical plan for awake or asleep tumour resection. RESULTS Analysis suggests language assessment scores may be influenced by a range of patient factors outside of the lesion location and its associated language deficits, including native language, age, ethnicity and religion. CONCLUSION Assessment scores influence a patient’s suitability for AC with language mapping and subsequent morbidity and mortality outcomes. Culture and sociodemographic background are integral to daily language use, and can therefore be expected to influence scores on language assessment tasks. This evaluation highlights the necessity for diversity of language use to be reflected in assessment tools used within an AC pathway. REFERENCES 1. Hervey-Jumper, S.L. and M.S. Berger, Maximizing safe resection of low- and high-grade glioma. JNO, 2016. 2. Wahab, S.S., P.L. Grundy, and C. Weidmann, Patient experience and satisfaction with awake craniotomy for brain tumours. BJNS, 2011. 3. Coello, A.F., et al., Selection of intraoperative tasks for awake mapping based on relationships between tumor location and functional networks: A review. JNS, 2013.
CaPaBLE - Assessing the Patient Generated Index Methodology in High Grade Glioma Patients and Caregivers
Authors: Lillie Pakzad-Shahabi, James Tallant, Kerlann Le Calvez, Mary Wells, Matt Williams
Journal: Neuro-Oncology (2022)

Abstract AIMS CaPaBLE tests the feasibility and acceptability of assessing quality of life (QoL) using the patient-, or caregiver-generated index (PGI/CaGI) methodology in patients with HGG and their caregivers. METHOD CaPaBLE, (https://www.isrctn.com/ISRCTN45555598), followed patients and/or their caregivers up to 6 months. Standard measures for patients were EORTC QLQ-C30/BN20, for caregivers the CarGOQOL questionnaire. The QoL topics raised through PGI/CaGI have been coded to the most relevant domain from their respective standard measure for an initial assessment of concordance. RESULTS 36 patients, 24 caregivers recruited to study; completing an average of 3 study assessment timepoints. PGI and CaGI generated 240 and 160 topics respectively. Patient concerns most frequently coded to EORTC domain of Role Functioning; Caregiver concerns mostly coded to CarGOQOL domain of Burden. Other topics frequently raised by patients such as the driving and sex life, and future planning by caregivers are not specifically raised in standard questionnaires. CONCLUSION Nearly all topics raised by patients and caregivers were mapped to the domains of their respective standard QoL measure. However, almost half of all topics raised by patients and caregivers mapped to a minority of the domains included in standard measures; whilst a notable number of topics are not specifically included in standard measures at all. This raises questions regarding the efficiency and relevance of such questionnaires to patient and caregivers’ daily lives.
MR Electrical Properties Tomography (MREPT) at 9.4T to Assess Treatment Response of Choline Kinase Inhibition on GL261 Glioblastoma
Authors: Tareq Alrashidi, Ahmed Nooradean, Sourav Bhaduri, Soham Mukherjee, Harish Poptani
Journal: Neuro-Oncology (2022)

Abstract AIMS To monitor changes in tissue-conductivity based MR parameter in response to JAS239 treatment in preclinical glioblastoma model. METHOD C57BL/6 mice were injected intracranially with 5x105 GL261 glioblastoma cells and tumours were observed on T2 weighted MRI. Mice were imaged on day 0 (baseline), day 3 , 6 of treatment and post-treatment day 10. For MREPT, multi-slice-multi-echo sequence was used. Laplacian algorithm was employed to obtain the phase-based MREPT image reconstruction. RESULTS Saline treated mice showed a greater increase in tumour volume compared to JAS239 treated animals with respect to baseline. Percentage changes in conductivity values with respect to baseline from saline treated mice were compared to JAS239 treated animals. JAS239 group showed a slight increase in mean conductivity on day 3 and 6 compared to saline group. There were no statistically (p&amp;gt; 0.05) significant differences between the two groups. 4 days after treatment completion (Day10), the mean of conductivity values of JAS239 treated animals compared to saline treated animals showed no statistically (p&amp;gt; 0.05) significant differences. These results may indicate that GL261 tumour model is treatment resistant. Our findings agree with a study conducted by Bhaduri et al, where tumours were treated with JAS239. CONCLUSION EPT technique provides unique data on tissue conductivity which can be used to improve the assessment of treatment response in glioblastoma. MREPT parameter might be insensitive to evaluate choline kinase inhibitor. For future work, this technique can be incorporated into multiparametric MRI to complement diffusion and perfusion-weighted imaging of assessing treatment response in glioblastoma.
IDHwt Glioblastomas Show Opposing Resistance Mechanisms Across Patients in Response to Standard Treatment
Authors: Georgette Tanner, Martina A Finetti, Steven Pollock, Nora Rippaus, Alexander-Francisco Bruns, Catherine Hogg, Alastair Droop, Anke Bruning-Richardson, Mathew Care, Joseph Wilkinson, Michael Jenkinson, Andrew Brodbelt, Aruna Chakrabarty, Azzam Ismail, Susan Short, Lucy Stead
Journal: Neuro-Oncology (2022)

Abstract AIMS Glioblastoma (GBM) is the most common primary malignant brain tumour in adults. Despite aggressive treatment, a resistant tumour recurs in practically all patients. We therefore aimed to better understand the mechanisms driving this treatment resistance through investigating changes in gene expression across pairs of primary and recurrent GBM tumours. METHOD We generated or acquired bulk tumour RNA sequencing data for primary and first recurrent tumours from 107 patients who received standard treatment. Differential expression analysis between primary and recurrent samples found that the most dysregulated genes were involved in neurodevelopment and neurodifferentiation. We therefore used a publicly available ChIP-seq database to identify DNA binding factors for which binding sites are enriched in the promotors of genes with the largest expression changes from primary to recurrent. RESULTS Jumonji and AT-Rich Interacting Domain 2 (JARID2) was the most strongly enriched for binding to promotors of dysregulated genes. 65 patients showed an up-regulation and 42 showed a down-regulation of genes bound by this protein. The same set of JARID2 bound genes were found to be dysregulated in each direction, and correlated with the largest source of variation between samples in their response to treatment. Further enrichment analyses indicated that ‘Up’ responders may resist treatment through reduced proliferation and increased interaction with the tumour microenvironment, whereas ‘Down’ responders instead rely on a shift to mesenchymal cell states. CONCLUSION These results indicate that GBM tumours can be split into two subtypes that transcriptionally reprogramme in different directions through treatment and may benefit from different treatment approaches.
Working Together to Accelerate the Preclinical to Clinical Translation of Drug Delivery Systems for Children’s Brain Tumours
Authors: Emma Campbell, Kristian Aquilina, Madhumita Dandapani, David Walker, Ruman Rahman
Journal: Neuro-Oncology (2022)

Abstract AIMS Several techniques, such as intra-cerebrospinal fluid chemotherapy, ultrasound-mediated blood-brain barrier disruption, convection enhanced delivery, polymer delivery systems, electric field therapy, and intra-arterial and intra-nasal chemotherapy, have the potential to transform the treatment of brain tumours in children. However, there have been very few clinical trials to evaluate these. We aim to address challenges in the pre-clinical to clinical research pathway for CNS drug delivery systems in order to increase the number of clinical trials in this area. METHOD In 2021, the CBTDDC (Children’s Brain Tumour Drug Delivery Consortium) and the ITCC (Innovative Therapies for Children with Cancer) brain tumour group established a Clinical Trials Working Group comprising international researchers and clinicians to address this issue. RESULTS This partnership highlighted the main challenges as: (1) a lack of specific funding for prototype development and/or scale-up for clinical trials; (2) difficulties in navigating the regulatory landscape; (3) lack of accurate preclinical models; and (4) increased need for multi-centric working. In response to this, we ran a workshop on ‘Clinical Trial Readiness’, attended by around 50 delegates (comprising clinicians, researchers, trial regulatory experts, policy makers, and representatives from funding organisations, brain tumour charities and industry). CONCLUSION We have now established speciality-specific working groups with the aim of producing recommendations around the use of preclinical models and drug delivery techniques according to brain tumour type. We have also created a ‘Roadmap’ document for preclinical to clinical translation, which will be freely shared with the neuro-oncology research community.
Transcriptome-wide Mendelian Randomisation Using Expression, Protein and Splicing Quantitative Trait Loci to Identify Novel Drug Targets Associated With Risk of Gliomagenesis
Authors: Zak Thornton, Jamie Robinson, Kathreena Kurian
Journal: Neuro-Oncology (2022)

Abstract AIMS To use two-sample Mendelian Randomisation to prioritise novel genes for drug targeting in glioma risk using expression, protein and splicing quantitative trait loci (eQTLs, pQTLs and sQTLs, respectively). METHOD We used genetic variants from GWAS to compare the effects of eQTLs, pQTLs and sQTLs on genetic liability to glioma risk (n=12,496). eQTL data was retrieved from the MetaBrain study of five different brain tissues (n=108 to 2,970). pQTL data was retrieved from the BrainQTL study of dorsolateral prefrontal cortex tissue (n = 330), and sQTL data was retrieved from Genotype-Tissue Expression (GTEx) Project (v8) of 13 brain tissues (n=114 to 209). SNPs which were trans-QTLs (&amp;gt;1 Mb) due to risk of horizontal pleiotropy, and greater than GWAS significance (P &amp;gt; 5 × 10-8) were excluded. Instruments were constructed using independent SNPs (r2 &amp;lt; 0.001). Results underwent relevant sensitivity analysis; colocalisation and Steiger filtering. RESULTS We found 123 MR associations for 28 genes with genetically predicted altered expression, protein or splicing levels affected risk of glioma. These included genes recurrently associated with glioma risk such as TERT, RTEL1, CDKN2A/B and EGFR, and novel putative genes; BTN3A2, GALNT6, GMPPB and FAIM. Following sensitivity analyses, we found that 58 MR associations for 25 genes had robust evidence. CONCLUSION We identified four novel associations not previously found in GWAS; BTN3A2 (6p22.2), FAIM (3q22.3), GALNT6 (12q13.13) and GMPPB (3p21.31) are implicated in glioma risk and are also not located on a known glioma risk locus. Further analysis is required to identify the suitability of these genes for drug targeting in glioma.
Treatment Response in GBM Cells Under Normoxic and Hypoxic Conditions
Authors: Becky Griggs, Simon J Allison, Anke Bruning-Richardson, Philippa Vaughn-Beaucaire
Journal: Neuro-Oncology (2022)

Abstract AIMS Glioblastomas (GBMs) are characterised by highly hypoxic regions and the ability to invade into healthy brain tissue promoting tumour dissemination and recurrence; the development of novel anti-migratory inhibitors to target cell invasion and recurrence must consider varying treatment responses in this tumour background. As proof of principle we investigated the anti-migratory activity of two, previously characterised, small molecule inhibitors under normoxic and hypoxic conditions. We hypothesised that anti-migratory drug activity is dependent on hypoxia levels. METHOD Glioma cell line U251 was exposed to BIO-indirubin and Y-27632 alone or in combination and activity was assessed in 2D scratch assays under normoxic (21% O2) and hypoxic (0.1% O2) conditions. Live cell imaging was performed and analysis was carried out using ImageJ. RESULTS Treatment with BIO, Y-27632 or in combination had a statistically significant effect on the inhibition of migration in normoxia and hypoxia (p=0.01); BIO inhibited migration and Y-27632 promoted migration under normoxia, whereas BIO maintained the anti-migratory effect under hypoxia, the effect of Y-27632 was switched towards anti-migratory activity and combination treatment potentiated. The effect of Y-27632 was concomitant with a phenotypic shift in cells under hypoxia from highly elongated to possessing shorter extensions. CONCLUSION An anti-migratory effect of Y-27632 on cell migration was induced under hypoxic conditions suggesting that the adoption of amoeboid migration by the cells allowed targeting migratory pathways under the control of RhoA and ROCK. This confirms that candidate drug activity must be assessed under both conditions to be considered as drugs complementary to chemotherapy as potential novel treatment option.
Intravoxel Incoherent Motion (IVIM) Diffusion-Weighted Imaging to Assess Treatment Response of Choline Kinase Inhibition on GL261 Mouse Glioblastoma
Authors: Nooradean Ahmed, Tareq Alrashidi, Sourav Bhaduri, Soham Mukherjee, Harish Poptani
Journal: Neuro-Oncology (2022)

Abstract AIMS To monitor changes in IVIM parameters in response to JAS239 treatment in preclinical glioblastoma models. METHOD C57BL/6 mice were injected intracranially with 5x105 GL261 glioblastoma cells and tumours were observed on T2 weighted MRI. Mice were imaged on day 0 (T0, baseline), day 3 (T3), 6 (T6) of treatment and post-treatment day 10 (T10). IVIM DWI was performed using a single-shot spin-echo echo planar sequence and processed using Matlab to acquire IVIM parameters of f, D, and D*. RESULTS Percentage changes in values with respect to baseline from saline treated control mice were compared to JAS239 treated animals with respect to baseline. Treated mice showed a slight increase in ADC and pseudo-diffusion on day 3 and day 6, with an increase in the perfusion fraction on day 6. However, no statistically significant difference between the two groups with respect to all 3 parameters (P&amp;gt;0.05). Analysis of the change in parameters post treatment (T10) also showed no statistically (P&amp;gt;0.05) significant difference between the mice treated with JAS239 and the control group treated with saline. CONCLUSION In this study of the IVIM based parameters, we observed no significant differences in these parameters which indicates that JAS329 may be ineffective in the treatment of GL261 tumours. There was no significant change in the diffusion and perfusion related parameters in the tumour region. IVIM parameters may be useful in studying the tumour microenvironment, however, these may not be sensitive in detecting tumour resistance to ChoK inhibitor therapies.
Clinical Evaluation of Gamma Knife Stereotactic Radiosurgery for Metastatic Disease in Elderly Patients
Authors: Mai Bishr, Cornel Tancu, Naomi Fersht, Neil Kitchen, Michael Kosmin
Journal: Neuro-Oncology (2022)

Abstract AIMS Gamma Knife Stereotactic Radiosurgery (GK-SRS) is an effective treatment option for limited brain metastases (BM); however, there is a paucity of data about its use in the elderly. Our aim is to explore the clinical outcomes of elderly cancer patients treated for BM with GK-SRS at our institution. METHOD We identified cancer patients aged ≥80 years at the time of receiving GK-SRS to BM between July 2017 and August 2021 from our electronic institutional database. Descriptive statistics and Kaplan–Meier analysis were performed using SPSS v.22. RESULTS A total of 24 patients were identified, with a median age of 83 years (range 80.1-89.9). The most common primary tumours were melanoma (58.4%) and lung (20.8%). In 14 patients (58%), multiple BM were treated simultaneously with a median of 2 lesions (range 2-15). The median target volume was 1.34cc (range 0.03-15.06). Prescribed doses ranged from 18Gy – 25Gy, prescribed to the 41-97% isodose line. After a median follow-up of 6.9 months (range 1.9-49.4 months), the local control rate (LCR) was 91.3% and the median post-GK-SRS overall survival was 9.8 months (95%CI 5.4-14.3). This compares to our previously published data from our wider GK-SRS-treated BM patient cohort, which showed a median survival of 15.6 months and LCR of 94.6%. CONCLUSION GK-SRS is an effective treatment modality for selected cancer patients with BM, including those over 80 years of age. Multi-institutional prospective studies are warranted to further explore the safety and functional outcomes of GK-SRS in elderly cancer patients.